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Erythrocyte β spectrin can be genetically targeted to protect mice from malaria

Lelliott, Patrick; Huang, Hong Ming; Dixon, Matthew W. A.; Namwar, Arman; Blanch, Adam. J; Rajagopal, Vijay; Tilley, Leann; Coban, Cevavyir; McMorran, Brendan; Foote, Simon; Burgio, Gaetan

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The malaria parasite hijacks host erythrocytes to shield itself from the immune system and proliferate. Red blood cell abnormalities can provide protection from malaria by impeding parasite invasion and growth within the cell or by compromising the ability of parasites to avoid host clearance. Here, we describe 2 N-ethyl-N-nitrosourea–induced mouse lines, SptbMRI26194 and SptbMRI53426, containing single-point mutations in the erythrocyte membrane skeleton gene, b spectrin (Sptb), which exhibit...[Show more]

dc.contributor.authorLelliott, Patrick
dc.contributor.authorHuang, Hong Ming
dc.contributor.authorDixon, Matthew W. A.
dc.contributor.authorNamwar, Arman
dc.contributor.authorBlanch, Adam. J
dc.contributor.authorRajagopal, Vijay
dc.contributor.authorTilley, Leann
dc.contributor.authorCoban, Cevavyir
dc.contributor.authorMcMorran, Brendan
dc.contributor.authorFoote, Simon
dc.contributor.authorBurgio, Gaetan
dc.date.accessioned2019-07-25T01:26:21Z
dc.date.available2019-07-25T01:26:21Z
dc.identifier.issn2473-9537
dc.identifier.urihttp://hdl.handle.net/1885/164701
dc.description.abstractThe malaria parasite hijacks host erythrocytes to shield itself from the immune system and proliferate. Red blood cell abnormalities can provide protection from malaria by impeding parasite invasion and growth within the cell or by compromising the ability of parasites to avoid host clearance. Here, we describe 2 N-ethyl-N-nitrosourea–induced mouse lines, SptbMRI26194 and SptbMRI53426, containing single-point mutations in the erythrocyte membrane skeleton gene, b spectrin (Sptb), which exhibit microcytosis but retain a relatively normal ratio of erythrocyte surface area to volume and are highly resistant to rodent malaria. We propose the major factor responsible for malaria protection is the specific clearance of mutant erythrocytes, although an enhanced clearance of ninfected mutant erythrocytes was also observed (ie, the bystander effect). Using an in vivo erythrocyte tracking assay, we established that this phenomenon occurs irrespective of host environment, precluding the involvement of nonerythrocytic cells in the resistance mechanism. Furthermore, we recapitulated this phenotype by disrupting the interaction between ankyrin-1 and b spectrin in vivo using CRISPR/Cas9 genome editing technology, thereby genetically validating a potential antimalarial target. This study sheds new light on the role of b spectrin during Plasmodium infection and highlights how changes in the erythrocyte cytoskeleton can substantially influence malaria susceptibility with minimal adverse consequences for the host.
dc.description.sponsorshipThis work was supported by the National Health and Medical Research Council (grants APP605524 , 4 90037 and 104 7082), the Australian Research Council (grants DP12010061 and FL150100106), the National Collaborative Research Infrastructure Strategy of Australia and the education investment fund from the Department of Innovation, Industry, Science and Research via the Australian Phenomics Network, and the Japan Society for the Promotion of Science Fellowship Program (grant S16706).
dc.format.mimetypeapplication/pdf
dc.language.isoen_AU
dc.publisherAmerican Society of Hematology
dc.rights© 2017 by The American Society of Hematology
dc.sourceBlood Advances
dc.titleErythrocyte β spectrin can be genetically targeted to protect mice from malaria
dc.typeJournal article
local.description.notesImported from ARIES
local.identifier.citationvolume1
dc.date.issued2018
local.identifier.absfor060599 - Microbiology not elsewhere classified
local.identifier.absfor060499 - Genetics not elsewhere classified
local.identifier.ariespublicationu4368888xPUB1
local.publisher.urlhttps://www.hematology.org/
local.type.statusPublished Version
local.contributor.affiliationLelliott, Patrick, College of Health and Medicine, ANU
local.contributor.affiliationHuang, Hong (Ming), College of Health and Medicine, ANU
local.contributor.affiliationDixon, Matthew W. A., Bio21 Institute
local.contributor.affiliationNamwar, Arman, Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, and Department of Biomedical Engineering, University of Melbourne, Melbourne, VIC, Australia;
local.contributor.affiliationBlanch, Adam. J, Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, and Department of Biomedical Engineering, University of Melbourne, Melbourne, VIC, Australia;
local.contributor.affiliationRajagopal, Vijay, Department of Biomedical Engineering, University of Melbourne, Melbourne, VIC, Australia
local.contributor.affiliationTilley, Leann, Bio21 Institute
local.contributor.affiliationCoban, Cevavyir, Osaka University
local.contributor.affiliationMcMorran, Brendan, College of Health and Medicine, ANU
local.contributor.affiliationFoote, Simon, College of Health and Medicine, ANU
local.contributor.affiliationBurgio, Gaetan, College of Health and Medicine, ANU
dc.relationhttp://purl.org/au-research/grants/nhmrc/605524
dc.relationhttp://purl.org/au-research/grants/nhmrc/490037
dc.relationhttp://purl.org/au-research/grants/nhmrc/1047082
dc.relationhttp://purl.org/au-research/grants/arc/FL150100106
local.bibliographicCitation.issue26
local.bibliographicCitation.startpage2624
local.bibliographicCitation.lastpage2636
local.identifier.doi10.1182/bloodadvances.2017009274
dc.date.updated2019-03-31T07:21:41Z
dcterms.accessRightsOpen Access
dc.provenancehttp://sherpa.ac.uk/romeo/issn/2473-9529/..."author can archive publisher's version/PDF" from SHERPA/RoMEO site (as at 25/07/19).
CollectionsANU Research Publications

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